Metrology and Nonlinear Acoustics Bioeffects of High Intensity Focused Ultrasound

描述（由申请人提供）：高强度聚焦超声（HIFU）是一种新兴的医疗技术，用于在mm尺寸的焦点“热点”内热消融靶组织，而不损伤介入组织。在最近的HIFU研究中，人们对使用纯机械破坏组织而不进行热凝固（组织破坏术）也有很大的兴趣。尽管高强度聚焦超声已成功用于治疗一些良性和恶性肿瘤，但由于安全性和有效性的监管标准不完善，该技术在临床上的广泛接受受到阻碍。目前的局限性包括：（a）缺乏既定的计量标准来表征HIFU场;（B）对高声强下的热和机械生物效应的机械理解不完整，这阻碍了给定暴露量信息的剂量量化;以及（c）临床挑战，例如治疗时间长、像肋骨这样的声学障碍以及具有成本效益的图像引导的有限可用性。该提案解决了这些限制，特别关注高功率水平的治疗。在最初几年的赠款，我们探索了HIFU治疗，利用非线性声学， 开发了用于表征强声场的计量工具。我们表明，冲击形成导致超声吸收比相同强度的谐波大10-100倍;因此，可以在毫秒内达到100 ℃的沸腾条件。我们开发了一种治疗方法，使用毫秒长的高压脉冲序列在焦点处传递冲击波。在这样的治疗方案中，组织消融被加速，沸腾的开始促进了超声的图像引导，并且组织损伤可以被控制为表现出机械损伤、热损伤或两者。该提案的具体目标建立在以前的工作，以推进非线性HIFU方法走向临床采用。在目标1中，我们将扩展HIFU换能器表征复杂的阵列源，我们将定义方法适用于标准的临床HIFU系统的性能评估。在目标2中，将建立高功率换能器，并将开发用于将暴露量与组织中的生物效应（离体）相关联的方法，用于一系列治疗方案，例如纯热，机械或组合。在目标3中，我们使用健康猪模型检查两个靶器官（肝脏和肾脏）中的肿瘤治疗。我们将使用代表现代临床系统的2D相控阵来实现一系列非线性HIFU协议。这些研究将解决肋骨和呼吸组织运动的干扰，允许在临床环境中仔细评估病变形成的精度和控制。以前针对高功率临床治疗的工作并没有涉及我们在这里提出的详细的基本特征。这项工作将通过提供准确评估HIFU暴露的工具，从而帮助制定监管指南，以促进FDA批准新的HIFU治疗，同时识别控制不良的系统，从而使公共卫生保健受益。这项工作也将推动HIFU向更快、更安全的临床治疗方向发展。

DESCRIPTION (provided by applicant): High Intensity Focused Ultrasound (HIFU) is an emerging medical technology for thermally ablating targeted tissue within a mm-size focal 'hot spot' without damaging intervening tissues. In recent HIFU studies, there has also been significant interest in using purely mechanical destruction of tissue without thermal coagulation (histotripsy). Despite successful use of HIFU for the treatment of some benign and malignant tumors, broader clinical acceptance of this technology is impeded by incomplete regulatory standards for safety and efficacy. Current limitations include (a) a lack of established metrology standards to characterize HIFU fields; (b) an incomplete mechanistic understanding of thermal and mechanical bioeffects at high acoustic intensities, which hinders the quantification of dose given exposimetry information; and (c) clinical challenges such as long treatment times, acoustic obstacles like ribs, and the limited availability of cost-effective image guidance. This proposal addresses these limitations with a particular focus on treatments at high power levels. In the initial years of the grant, we explored HIFU treatments that utilize nonlinear acoustics and developed metrology tools for characterizing intense acoustic fields. We showed that shock formation leads to ultrasound absorption that is 10-100 times greater than for harmonic waves of the same intensity; consequently, boiling conditions at 100¿C can be reached within milliseconds. We developed a treatment method that uses sequences of millisecond-long, high-pressure pulses to deliver shocks waves at the focus. In such treatment regimes, tissue ablation is accelerated, the initiation of boiling facilitates image guidance with ultrasound, and tissue lesions can be controlled to exhibit mechanical damage, thermal damage, or both. The specific aims of this proposal build upon the previous work to advance nonlinear HIFU methods toward clinical adoption. In Aim 1, we will extend HIFU transducer characterization to complex array sources, and we will define methods suitable for standard use in performance assessment of clinical HIFU systems. In Aim 2, high power transducers will be built and the methods for correlating exposimetry with bioeffects in tissue (ex vivo) will be developed for a range of therapeutic regimes such as purely thermal, mechanical, or combined. In Aim 3, we examine tumor treatment in two target organs, the liver and the kidney, using a healthy porcine model. We will implement a range of nonlinear HIFU protocols using a 2D phased array representative of modern clinical systems. These studies will address interference from ribs and respiratory tissue motion, allowing careful assessment of the precision and control of lesion formation in a clinical setting. Previous work targeted at high-power clinical treatments has not involved the detailed fundamental characterizations that we propose here. The work will benefit public health care by providing tools for accurate evaluation of HIFU exposure, thereby aiding the development of regulatory guidelines to facilitate FDA approval of new HIFU therapies while identifying poorly controlled systems. The work will also advance HIFU toward faster and safer clinical treatments.